Pharmacogenetics involves the study of host susceptibility and environmental exposures in cancer development. The unique contribution of this discipline is that common genes are studied, and the role of the environment is more explicit because the mechanism of the putative polymorphic gene of interest is known, and the study base is the population rather than the family. We are examining a variety of putative susceptibility genes in a case-control study of lung cancer. We have observed increased risk of lung cancer in GSTM1 null individuals. Other genes including CYP1A1, CYP2D6, CYP2A6, NAT2, GSTP1, and the Ah receptor are under investigation. Putative genetic susceptibility markers are also the focus of study with regard to other cancers including head and neck, nasopharyngeal, prostate, breast, and colon. In a study of oral cancer in Puerto Rico we identified increased risk in heavy alcohol drinkers who possessed a variant of the ADH3 (alcohol dehydrogenase) gene with a greater capacity to convert alcohol to acetaldehyde. We originally reported one of the first relationships of exposure-gene effects relevant to cancer with a description of the relationship of the N-acetyltransferase phenotype (NAT2/genotype), 4- aminobiphenyl hemoglobin adducts, and tobacco consumption. We are examining the relationship of other carcinogenic exposures to genetic factors including the environmental toxicant dioxin (in the exposed population of Seveso Italy) and nicotine (in a smoking cessation study). In the validation component of a study designed to identify susceptibility factors for dioxin-related illness in the exposed population of Seveso, Italy, we have observed that measured dioxin levels in women are significantly elevated compared to men. The relationship of effect markers (i.e., p53 or K-ras mutations in tumor tissue) to both genetic factors and exposures is being studied in well-characterized series of colon, gastric and lung cancer.